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1.
J Am Chem Soc ; 145(3): 1955-1963, 2023 Jan 25.
Article in English | MEDLINE | ID: mdl-36625653

ABSTRACT

As one of the most typical bioorthogonal reactions, the Cu(I)-catalyzed azide-alkyne 1,3-cycloaddition (CuAAC) reaction has received worldwide attention in intracellular transformation of prodrugs due to its high efficiency and selectivity. However, the exogenous Cu catalysts may disturb Cu homeostasis and cause side effects to normal tissues. What is more, the intratumoral Cu(I) is insufficient to efficiently catalyze the intracellular CuAAC reaction due to oncogene-induced labile Cu(I) deficiency. Herein, in order to boost the endogenous Cu(I) level for intracellular drug synthesis through the bioorthogonal reaction, a self-adaptive bioorthogonal catalysis system was constructed by encapsulating prodrugs and sodium ascorbate within adenosine triphosphate aptamer-functionalized metal-organic framework nanoparticles. The system presents specificity to tumor cells and does not require exogenous Cu catalysts, thereby leading to high anti-tumor efficacy and minimal side effects both in vitro and in vivo. This work will open up a new opportunity for developing biosafe and high-performance bioorthogonal catalysis systems.

2.
Chem Commun (Camb) ; 59(8): 1078-1081, 2023 Jan 24.
Article in English | MEDLINE | ID: mdl-36621881

ABSTRACT

Here, we provide an out-of-the-box G-quadruplex (G4) targeting-based strategy for rescuing mitochondrial dysfunction in Alzheimer's disease. We predict and verify the presence of G4s within the promoter of an ageing epigenetic regulator BAZ2B. G4-specific ligands targeting BAZ2B G4s could significantly down-regulate the BAZ2B expression and relieve mitochondrial dysfunction. Therefore, this work may provide a new way of rescuing mitochondrial dysfunction in AD by targeting G4s in a specific ageing epigenetic regulator promoter.


Subject(s)
Alzheimer Disease , G-Quadruplexes , Transcription Factors, General , Humans , Promoter Regions, Genetic , Mitochondria , Epigenesis, Genetic , Ligands
3.
Angew Chem Int Ed Engl ; : e202218159, 2022 Dec 28.
Article in English | MEDLINE | ID: mdl-36578232

ABSTRACT

Bioorthogonal catalysis mediated by Pd-based transition metal catalysts has sparked increasing interest in combating diseases. However, the catalytic and therapeutic efficiency of current Pd0 catalysts is unsatisfactory. Herein, inspired by the concept that ligands around metal sites could enable enzymes to catalyze astonishing reactions by changing their electronic environment, a LM-Pd catalyst with liquid metal (LM) as an unusual modulator has been designed to realize efficient bioorthogonal catalysis for tumor inhibition. The LM matrix can serve as a "ligand" to afford an electron-rich environment to stabilize the active Pd0 and promote nucleophilic turnover of the π-allylpalladium species to accelerate the uncaging process. Besides, the photothermal properties of LM can lead to the enhanced removal of tumor cells by photo-enhanced catalysis and photothermal effect. We believe that our work will broaden the application of LM and motivate the design of bioinspired bioorthogonal catalysts.

4.
Small ; : e2206707, 2022 Dec 21.
Article in English | MEDLINE | ID: mdl-36541749

ABSTRACT

Multi-nanozymes are widely applied in disease treatment, biosensing, and other fields. However, most current multi-nanozyme systems exhibit only moderate activity since reaction microenvironments of different nanozyme are often distinct or even incompatible. Conventional assemble strategies are inapplicable for designing multi-nanozymes consisting of incompatible nanozymes. Herein, a versatile fiber-based compartmentalization strategy is developed to construct multi-nanozyme system capable of simultaneously performing incompatible reactions. In this system, the incompatible nanozymes are spatially distributed in distinct compartmentalized fibers, where different microenvironments can be tailored by controlling the doping reagent, endowing each nanozymes with the preferential microenvironments to exhibit their highest activity. As a proof of concept, pH-incompatible peroxidase-like and catalase-like catalytic reactions are tested to verify the feasibility of this strategy. By doping with benzoic acid in the desired location, the two pH-incompatible nanozymes can work simultaneously without interference. Further, it is demonstrated that the oxygen supply and antimicrobial power of the integrated platform can be applied for accelerating diabetic wound healing. It is hoped that this work provides a way to integrate incompatible nanozyme and broadens the application potential of multi-nanozymes.

5.
ACS Nano ; 2022 Nov 18.
Article in English | MEDLINE | ID: mdl-36398983

ABSTRACT

Pd-catalyzed bioorthogonal bond cleavage reactions are widely used and frequently reported. It is circumscribed by low reaction efficiency, which may encumber the therapeutic outcome when applied to physiological environments. Herein, an NIR-II light promoted integrated catalyst (CuS@PDA/Pd) (PDA - polydopamine) is designed to accelerate the reaction efficiency and achieve a dual bioorthogonal reaction for combination therapy. As NIR-II light can penetrate deeply into tissue, the Pd-mediated cleavage reaction can be promoted both in vitro and in vivo by the photothermal properties of CuS, beneficial to orthotopic 4T1 tumor treatment. In addition, CuS also catalyzes the synthesis of active resveratrol analogs by the CuAAC reaction. These simultaneously produced anticancer agents result in enhanced antitumor cytotoxicity in comparison to the single treatments. This is a fascinating study to devise an integrated catalyst boosted by NIR-II light for dual bioorthogonal catalysis, which may provide the impetus for efficient bioorthogonal combination therapy in vivo.

6.
ACS Nano ; 2022 Nov 17.
Article in English | MEDLINE | ID: mdl-36394517

ABSTRACT

As a burgeoning bioorthogonal reaction, the fluoride-mediated desilylation is capable of prodrug activation. However, due to the reactions lack of cell selectivity and unitary therapy modality, this strongly impedes their biomedical applications. Herein, we construct a cancer cell-selective biomimetic metal-organic framework (MOF)-F platform for prodrug activation and enhanced synergistic chemodynamic therapy (CDT). With cancer cell membranes camouflage, the designed biomimetic nanocatalyst displays preferential accumulation to homotypic cancer cells. Then, pH-responsive nanocatalyst releases fluoride ions and ferric ions. For activation of our designed prodrug tert-butyldimethyl silyl (TBS)-hydroxycamptothecin (TBSO-CPT), fluoride ions can desilylate TBS and cleave the designed silyl ether linker to synthesize the OH-CPT (10-hydroxycamptothecin) drug molecule, which effectively kills cancer cells. Intriguingly, the bioorthogonal-synthesized OH-CPT drug upregulates intracellular H2O2 by activating nicotinamide adenine dinucleotide phosphate oxidase (NOX), amplifying the released iron induced Fenton reaction for synergistic CDT. Both in vitro and in vivo studies demonstrate our strategy presents a versatile fluoride-activated bioorthogonal catalyst for cancer cell-selective drug synthesis. Our work may accelerate the biomedical applications of fluoride-activated bioorthogonal chemistry.

7.
J Am Chem Soc ; 144(42): 19611-19618, 2022 10 26.
Article in English | MEDLINE | ID: mdl-36240426

ABSTRACT

Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction has been widely regarded as a promising avenue in bioorthogonal chemistry. The emerging heterogeneous copper catalysts have been developed with a series of exciting applications such as in situ activation of prodrugs because of their excellent stability and biocompatibility. However, due largely to the complex biophysical barriers in living organisms, most synthetic bioorthogonal drugs cannot penetrate deep pathological tissues. Especially in biofilm-associated infections, the biofilms severely block the penetration of traditional antimicrobial agents and increase the antibiotic resistance, which makes it extremely difficult to eliminate the biofilms. Inspired by self-propelled biological motors, such as enzymes, herein, we develop a NIR light-controllable carbonaceous nanocalabash (CNC) motor catalyst with good biocompatibility for active targeted synthesis of drugs inside the biofilms as a robust general-purpose bioorthogonal platform. Under the NIR laser, the CNC motor catalysts display a rapid autonomous motion and generate active molecules in the deep biofilm layers, removing the biofilms and eradicating the shielded bacteria. Our work will shed light on developing a robust bioorthogonal platform for active targeted synthesis of drugs in deep-layered living systems.


Subject(s)
Azides , Prodrugs , Azides/chemistry , Copper/chemistry , Click Chemistry , Cycloaddition Reaction , Alkynes/chemistry , Catalysis
8.
Cell Discov ; 8(1): 86, 2022 Sep 06.
Article in English | MEDLINE | ID: mdl-36068208

ABSTRACT

The ongoing COVID-19 pandemic has continued to affect millions of lives worldwide, leading to the urgent need for novel therapeutic strategies. G-quadruplexes (G4s) have been demonstrated to regulate life cycle of multiple viruses. Here, we identify several highly conservative and stable G4s in SARS-CoV-2 and clarify their dual-function of inhibition of the viral replication and translation processes. Furthermore, the cationic porphyrin compound 5,10,15,20-tetrakis-(N-methyl-4-pyridyl)porphine (TMPyP4) targeting SARS-CoV-2 G4s shows excellent antiviral activity, while its N-methyl-2-pyridyl positional isomer TMPyP2 with low affinity for G4 has no effects on SARS-CoV-2 infection, suggesting that the antiviral activity of TMPyP4 attributes to targeting SARS-CoV-2 G4s. In the Syrian hamster and transgenic mouse models of SARS-CoV-2 infection, administration of TMPyP4 at nontoxic doses significantly suppresses SARS-CoV-2 infection, resulting in reduced viral loads and lung lesions. Worth to note, the anti-COVID-19 activity of TMPyP4 is more potent than remdesivir evidenced by both in vitro and in vivo studies. Our findings highlight SARS-CoV-2 G4s as a novel druggable target and the compelling potential of TMPyP4 for COVID-19 therapy. Different from the existing anti-SARS-CoV-2 therapeutic strategies, our work provides another alternative therapeutic tactic for SARS-CoV-2 infection focusing on targeting the secondary structures within SARS-CoV-2 genome, and would open a new avenue for design and synthesis of drug candidates with high selectivity toward the new targets.

9.
Proc Natl Acad Sci U S A ; 119(36): e2204725119, 2022 09 06.
Article in English | MEDLINE | ID: mdl-36037371

ABSTRACT

Precise manipulation of chromatin folding is important for understanding the relationship between the three-dimensional genome and nuclear function. Existing tools can reversibly establish individual chromatin loops but fail to manipulate two or more chromatin loops. Here, we engineer a powerful CRISPR system which can manipulate multiple chromatin contacts using bioorthogonal reactions, termed the bioorthogonal reaction-mediated programmable chromatin loop (BPCL) system. The multiinput BPCL system employs engineered single-guide RNAs recognized by discrete bioorthogonal adaptors to independently and dynamically control different chromatin loops formation without cross-talk in the same cell or to establish hubs of multiway chromatin contacts. We use the BPCL system to successfully juxtapose the pluripotency gene promoters to enhancers and activate their endogenous expression. BPCL enables us to independently engineer multiway chromatin contacts without cross-talk, which provides a way to precisely dissect the high complexity and dynamic nature of chromatin folding.


Subject(s)
Chromatin Assembly and Disassembly , Chromatin , Clustered Regularly Interspaced Short Palindromic Repeats , Chromatin/genetics , Chromosomes , Enhancer Elements, Genetic , Genome , Promoter Regions, Genetic
11.
Angew Chem Int Ed Engl ; 61(43): e202208757, 2022 10 24.
Article in English | MEDLINE | ID: mdl-35920081

ABSTRACT

As a neat combination of the characteristics of enzymatic activity and nanomaterials, nanozymes have attracted much attention. Although tremendous effort has been devoted to developing nanozymes with high catalytic activity, substrate selectivity is often overlooked in the construction of nanozymes. With their subtly evolving structures, natural enzymes generally possess high selectivity for chiral substrates which play important roles in biosynthesis and biomedical applications. However, the rational construction of nanozymes with high enantioselectivity remains a significant challenge. In this Minireview, we provide an overview of recent advances in strategies for the synthesis of chiral nanozymes and their enantioselective biological catalysis. We further focus on current challenges, potential solutions, and future developing trends of chiral nanozyme-based enantioselective biological catalysis. There is plenty of room to explore. This Minireview will provide new insights into the development of chiral nanozymes and their applications.


Subject(s)
Nanostructures , Stereoisomerism , Catalysis , Nanostructures/chemistry
12.
Angew Chem Int Ed Engl ; 61(38): e202204291, 2022 09 19.
Article in English | MEDLINE | ID: mdl-35912893

ABSTRACT

The intelligent nanomachine usually has a control center to carry out self-regulation. Unfortunately, most of the nanomaterials for chemodynamic therapy (CDT) do not have such a control center to sense and process the chemical or biological signals, which greatly weakens the selectivity and efficiency of CDT. To address this problem, here an intelligent nanomachine was constructed with a DNAzyme logic gate as the control center, and metal organic framework as the actuator. The well-designed nanomachine showed an enhanced killing effect on cancer cells but posed no harm to normal cells, acquiring better selectivity than clinical chemotherapy drugs (doxorubicin and cisplatin). To the best of our knowledge, this is the first reported cell-specific CDT by the guidance of DNAzyme logic gate. Our work highlights the great potential of DNAzymes in intelligent response networks, and extends the implementation of nanomachines in precision medicine.


Subject(s)
DNA, Catalytic , Logic
13.
Chem Sci ; 13(26): 7829-7836, 2022 Jul 06.
Article in English | MEDLINE | ID: mdl-35865897

ABSTRACT

As one of the representative bioorthogonal reactions, the copper-catalyzed click reaction provides a promising approach for in situ prodrug activation in cancer treatment. To solve the issue of inherent toxicity of Cu(i), biocompatible heterogeneous copper nanoparticles (CuNPs) were developed for the Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. However, the unsatisfactory catalytic activity and off-target effect still hindered their application in biological systems. Herein, we constructed a DNAzyme-augmented and targeted bioorthogonal catalyst for synergistic cancer therapy. The system could present specificity to cancer cells and promote the generation of Cu(i) via DNAzyme-induced value state conversion of DNA-templated ultrasmall CuNPs upon exposure to endogenous H2O2, thereby leading to high catalytic activity for in situ drug synthesis. Meanwhile, DNAzyme could produce radical species to damage cancer cells. The synergy of in situ drug synthesis and chemodynamic therapy exhibited excellent anti-cancer effects and minimal side effects. The study offers a simple and novel avenue to develop highly efficient and safe bioorthogonal catalysts for biological applications.

15.
Chem Sci ; 13(22): 6704-6714, 2022 Jun 07.
Article in English | MEDLINE | ID: mdl-35756527

ABSTRACT

Ultrasound (US)-mediated sonodynamic therapy (SDT) has emerged as a spatiotemporally controllable therapeutic modality in combating cancer because of its high tissue-penetration depth and minimal invasiveness. However, the elevated nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant program in cancer cells can serve as a chief reactive oxygen species (ROS) detoxification system to alleviate oxidative injury and promote tumorigenesis, and thus greatly antagonize the therapeutic efficacy of ROS-mediated anticancer therapies. Herein, we report that vanadium carbide MXene-derived carbon dots (PMQDs) can act as high-efficacy sonosensitizers to efficiently generate ROS upon US irradiation and simultaneously hinder the Nrf2 antioxidant program for enhanced sonodynamic therapy of cancer. These PMQDs show superior US-triggered ROS generating ability because of their efficient migration/separation of electron-hole pairs and narrow bandgap. Importantly, these PMQDs can serve as efficient redox homeostasis regulators to perturb the Nrf2 antioxidant mechanism and thus reduce its effects on ROS neutralization for enhanced SDT efficacy. Overall, the present study will not only provide a new paradigm to augment SDT by perturbing the Nrf2 antioxidant program, but also give valuable insights into developing high-efficacy MXene-derived nanoagents for cancer therapy.

16.
Chem Commun (Camb) ; 58(55): 7634-7637, 2022 Jul 07.
Article in English | MEDLINE | ID: mdl-35713636

ABSTRACT

A magnetoelectrically ignited nanozyme-eel was developed, which could generate abundant surface charges upon the ignition of an alternating magnetic field, leading to a controllable electron transport burst between the nanozyme-eel and bacteria for the eradication of bacterial biofilms.


Subject(s)
Anti-Bacterial Agents , Biofilms , Animals , Bacteria , Eels
17.
Angew Chem Int Ed Engl ; 61(28): e202201485, 2022 07 11.
Article in English | MEDLINE | ID: mdl-35385196

ABSTRACT

Herein we present a new way to encapsulate neural stem cells (NSCs) by using hydrogen-bonded organic frameworks (HOFs) to overcome the common causes of low therapeutic efficacy during NSC transplantation: 1) loss of fundamental stem cell properties, "stemness", before transplantation, 2) cytomembrane damage during transplantation, and 3) apoptosis due to oxidative stress after transplantation. Porous carbon nanospheres (PCNs) are doped into the HOF shell during the process of mineralization to endow the cellular exoskeletons with hierarchical hydrogen bonds, and the ability to resist oxidative stress due to the catalase and superoxide dismutase-like activities of PCN. Under NIR-II irradiation, thermal-responsive hydrogen bonds dissociate to release NSCs. Stereotactic transplanting encapsulated NSC into the brain of an Alzheimer's disease (AD) mouse model further verifies that our design can enhance NSC viability, promote neurogenesis, and ameliorate cognitive impairment. As the first example of using HOFs to encapsulate NSCs, this work may inspire the design of HOF-based exoskeletons to ameliorate neurogenesis and cognitive behavioral symptoms associated with AD.


Subject(s)
Alzheimer Disease , Neural Stem Cells , Animals , Cell Encapsulation , Hydrogen , Hydrogen Bonding , Mice , Neural Networks, Computer
18.
Nat Commun ; 13(1): 1459, 2022 03 18.
Article in English | MEDLINE | ID: mdl-35304487

ABSTRACT

As one of the typical bioorthogonal reactions, copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction holds great potential in organic synthesis, bioconjugation, and surface functionalization. However, the toxicity of Cu(I), inefficient catalytic activity, and the lack of cell specific targeting of the existing catalysts hampered their practical applications in living systems. Herein, we design and construct a DNA-based platform as a biocompatible, highly efficient, and precisely targeted bioorthogonal nanocatalyst. The nanocatalyst presents excellent catalytic efficiency in vitro, which is one order of magnitude higher than the commonly used catalyst CuSO4/sodium ascorbate. The theoretical calculation further supports the contribution of DNA structure and its interaction with substrates to the superior catalytic activity. More importantly, the system can achieve efficient prodrug activation in cancer cells through cell type-specific recognition and produce a 40-fold enhancement of transformation compared to the non-targeting nanocatalyst, resulting in enhanced antitumor efficacy and reduced adverse effects. In vivo tumor therapy demonstrates the safety and efficacy of the system in mammals.


Subject(s)
Azides , Click Chemistry , Alkynes/chemistry , Animals , Azides/chemistry , Catalysis , Click Chemistry/methods , Copper/chemistry , Cycloaddition Reaction , DNA , Mammals
19.
ACS Nano ; 16(3): 4228-4238, 2022 03 22.
Article in English | MEDLINE | ID: mdl-35213138

ABSTRACT

The high glutathione (GSH) content in tumor cells strongly affects the efficiency of chemodynamic therapy (CDT). Despite devoted efforts, it still remains a formidable challenge for manufacturing a tumor-specific CDT with rapid and thorough depletion of GSH. Herein, a multistage GSH-consuming and tumor-specific CDT is presented. By consuming the reserved GSH and inhibiting both the raw materials and energy supply of GSH synthesis in cancer cells, it achieves highly potent GSH exhaustion. Our used glycolysis inhibitor cuts off the specific glycolysis of tumor cells to increase the sensitivity to CDT. Furthermore, the starvation effect of glycolysis inhibitor can stimulate the protective mode of normal cells. Since the glycolysis inhibitor and nanocarrier are responsive to tumor microenvironment, this makes CDT more selective to tumor cells. Our work not only fabricates nanomedicine with GSH exhausted function for highly potent CDT but also uses metabolic differences to achieve tumor-specific therapy.


Subject(s)
Nanoparticles , Neoplasms , Cell Line, Tumor , Glutathione/metabolism , Humans , Hydrogen Peroxide/pharmacology , Nanomedicine , Neoplasms/drug therapy , Tumor Microenvironment
20.
Angew Chem Int Ed Engl ; 61(16): e202115336, 2022 04 11.
Article in English | MEDLINE | ID: mdl-35137505

ABSTRACT

Post-translational modification (PTM) of protein can significantly change protein conformation and function. Inspired by the natural PTM, we present a new approach to inhibit amyloid aggregation by chemical PTM modification. Polyoxometalates (POMs) were used as examples of inhibitors of ß-amyloid peptide (Aß) aggregation to illustrate the chemical PTM method. After the POMs were modified with thiazolidinethione (TZ), the resulting POMD-TZ acted as a chemical PTM agent and could covalently modify Aß site-selectively at Lys16. Multiple biophysical techniques and biochemical assays have been employed to show the superiority of the chemical PTM method compared to traditional Aß inhibitors. Since Aß oligomers are more cytotoxic, we further functionalized POMD-TZ with an Aß-targeted peptide and a fluorescent probe to obtain an "Aß oligomer sensitive" probe. The use of PTM agents for the site-directed chemical modification of proteins provides a new way to regulate amyloid aggregation.


Subject(s)
Alzheimer Disease , Amyloidosis , Alzheimer Disease/metabolism , Amyloid/chemistry , Amyloid beta-Peptides/metabolism , Anions , Humans , Peptide Fragments/chemistry , Polyelectrolytes
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